International Journal of Cardiology 162 (2013) 73–76

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Review

Highlights of the mechanistic and therapeutic cachexia and sarcopenia research 2010
to 2012 and their relevance for cardiology
Markus S. Anker a, Stephan von Haehling b, Jochen Springer c, Maciej Banach d, Stefan D. Anker a, b,⁎
a
Center for Clinical and Basic Research, IRCCS San Raffaele, Rome, Italy
b
Applied Cachexia Research, Department of Cardiology, Charité, Campus Virchow-Klinikum, Berlin, Germany
c
Applied Cachexia Research, Center for Cardiovascular Research, Charité, Campus Mitte, Berlin, Germany
d
Department of Hypertension, Medical University of Lodz, Lodz, Poland

a r t i c l e i n f o a b s t r a c t

Article history: Sarcopenia and cachexia are significant medical problems with a high disease related burden in cardiovascu-
Received 19 October 2012 lar illness. Muscle wasting and weight loss are very frequent particularly in chronic heart failure and they re-
Accepted 20 October 2012 late to poor prognosis. Although clinically largely underestimated, the fields of cachexia and sarcopenia are of
Available online 20 November 2012
great relevance to cardiologists.
In cachexia and sarcopenia a significant number of research publications related to basic science questions of
Keywords:
Cachexia
muscle wasting and lipolysis were published between 2010 and 2012. Recently, the two processes of muscle
Sarcopenia wasting and lipolysis were found to be closely linked. Treatment research in pre-clinical models involves
Muscle wasting studies on a number of different therapeutic entities, including ghrelin, selective androgen receptor modula-
Mechanism tors (SARMs), as well as drugs targeting myostatin or melanocortin-4. In the human setting, studies using
Therapy enobosarm (a SARM) and anamorelin (ghrelin) are in phase III.
Cardiovascular illness The last 3 years has seen significant efforts to define the field using consensus statements. In the future, these
Heart failure definitions should also be considered for guidelines and treatment trials in cardiovascular medicine. The cur-
rent review aims to summarize important information and development in the fields of muscle wasting,
sarcopenia and cachexia focussing on findings in cardiovascular research, in order for cardiologists to have
a better understanding of the progress in the still not well enough known field.
© 2012 Published by Elsevier Ireland Ltd.

1. Introduction
The last decades has seen increasing interest in muscle wasting
[1–5] and cachexia [6–16] research in chronic diseases and ageing.
Indeed, both are significant medical problems with a high disease re-
lated burden on symptoms, quality of life and prognosis of patients
[17–19] and with high socioeconomic expense [20]. Muscle wasting
in general, sarcopenia, lipolysis and cachexia are very active research
fields with great medical relevance [21–23]. New research is abundant
and many comprehensive review articles are written to cover the new
findings on mechanisms and pathophysiology [24,25] as well as symp-
toms [26,27], nutritional issues [28,29], and new therapeutic options
[30–33]. In this review we aimed to summarize the most important in-
formation on muscle wasting, sarcopenia and cachexia focussing on
findings in cardiovascular research, in order for cardiologists to have
a better understanding of the progress in this still not well enough
⁎ Corresponding author at: Applied Cachexia Research, Department of Cardiology,
Charité Berlin, Campus Virchow-Klinikum, D-13353 Berlin, Germany. Tel.: +49 30 450
553463; fax: +49 30 450 553951.
E-mail address: s.anker@cachexia.de (S.D. Anker).
known field. In order to reach the wide group of physicians and
researchers we have decided to publish this review simultaneously
in two renowned journals (wide-scope and cardiologist ones).
2. Search strategy
We searched the electronic databases MEDLINE, EMBASE and
SCOPUS (January 2010 to October 2012). Additionally, abstracts from
national and international cardiovascular meetings were searched.
The main search terms were: cachexia, sarcopenia, muscle wasting,
mechanism, therapy, cardiovascular illness, and heart failure.
Muscle wasting is not only seen in chronically ill patients, but is
also prominent in acute and critical illnesses, including sepsis and
septic shock [34], and in hospitalised patients with acute and severe
lung diseases [35]. Patients with chronic heart failure were recently
found to be affected by muscle wasting fulfilling the criteria of
sarcopenia in 19.5% of a prospectively enrolled cohort of patients
with stable disease [36]. Cachexia, on the other hand, is frequent
in chronic kidney disease (CKD) [25,37–39] and as part of the
cardio-renal syndrome also affecting heart failure (HF) patients regu-
larly [40–42]. Cachexia is also a significant problem in advanced heart
disease itself [43] and is related to co-morbidities like diabetes

0167-5273/$ – see front matter © 2012 Published by Elsevier Ireland Ltd.

http://dx.doi.org/10.1016/j.ijcard.2012.10.018
74 M.S. Anker et al. / International Journal of Cardiology 162 (2013) 73–76
mellitus and chronic inflammation [44]. Abnormal cardiac parame-
ters are seen in cachexia and may be associated with abnormal myo-
cardial perfusion [45].
Research on muscle wasting is greatly focusing not only on regula-
tors such as myostatin [46], the ubiquitin–proteasome pathway [47],
and free-radical production [48], but also on novel treatment ap-
proaches including the use of bile acids [49]. The latter has also
been tested in humans with chronic heart failure (CHF) and showed
improvements of endothelial function in arms and legs [50]. Limb
anatomical changes may also cause peripheral neuropathy, which in
turn has been shown to relate to poor quality of life [51]. Adaptive
mechanisms in skeletal muscle are complex, and involve the whole
body which develops anabolic/catabolic imbalance, anabolic failure
and hypogonadism, which have been convincingly shown in CHF
[52–54]. Other pathogenetic factor studies include sirtuin 1, which
has been suggested to be a relevant mechanistic factor in the develop-
ment of insufficient regeneration of skeletal muscle in cancer cachex-
ia [55]. Desmin and tissue zinc redistribution are additional factors
investigated for their role in muscle wasting [56,57]. Other important
fields of research are related to metabolic syndrome and insulin resis-
tance [58–61] as well as heat shock protein 72 [62], muscle stem cell
function [63] and related telomere alterations [64]. The role of genetic
factors is less well understood at this stage, but related research
efforts are underway [44].
Research on lipolysis [65] is a young but strongly evolving field.
There is strong interaction between lipolysis and muscle wasting
[66–68]. This may also be relevant in heart disease [69].
Biomarker research in the field of muscle wasting is active [70,71].
Serum creatinine levels are understood to be an unspecific marker of
muscle wasting [72], but recently a more specific marker (C-terminal
agrin fragment) was described [73]. Built on a consensus conference
that took place in Toulouse in 2011, recently a consensus paper on
blood analysis based as well as imaging based biomarkers defining
sarcopenia was published [74]. Before such biomarkers can be consid-
ered clinically (outcome) validated, successful clinical intervention
phase III trials are needed to validate these biomarkers.
Interventional studies in the pre-clinical setting are frequently
reported and include studies investigating the insulin-like growth
factor [75], ghrelin and ghrelin analogues [76,77], as well as specific
androgen receptor modulators (SARMs) [78], and myostatin anti-
bodies [79]. In addition, pre-clinical models suggest that treatments
to block the effects mediated via the melanocortin-4 receptor may be
useful in cachexia and muscle wasting [80]. The melanocortin-4 recep-
tor antagonist BL-6020/979 is orally available and ready for human
testing [32,81]. The results so far are promising. Several other such com-
pounds are in development [82]. Anabolic drugs are potentially of great
relevance to HF where muscle wasting is highly prevalent [22]. Testos-
terone has already been tested and results are promising [83].
In recent years, several interventional trials in humans have been
performed, but for a number of them no final publications do yet exist
and we have to rely on meeting reports at conferences and press re-
leases. Two promising drug treatment approaches are now in phase
III clinical testing [84]. The SARM GTx-024 (enobosarm) [85] is tested
in two trials of 300 patients as to whether it can prevent or treat mus-
cle wasting in non-small cell lung cancer. The two primary endpoints
include changes in lean mass as well as changes in stair-climbing
power [86]. The second trial programme includes 2 trials of 477
patients each to investigate whether an orally available ghrelin
(anamorelin) can positively impact on the disease progression of
cachexia in non-small cell lung cancer [87]. The two primary endpoints
include changes in lean mass as well as changes in hand-grip strength,
which will also have relevance in future heart failure trials. Results for
these clinical trial programmes are expected to be available in 2014.
From a cardiological standpoint, it is interesting to note that even
cardiovascular drugs are now in clinical testing in cachexia. MT-102 is
an anabolic/catabolic transforming agent with beta-1-blocking activity
and it has direct anabolic and appetite stimulating effects in animal
studies [88]. It is now investigated in 132 patients with cachexia due
to lung cancer or colorectal cancer [88]. Of interest, in the past an angio-
tensin converting enzyme inhibitor (imidapril) was also investigated
for use in cancer cachexia. It showed some promising results, but devel-
opment programmes were not completed due to lack of funding [89].
One treatment alone may not be sufficient to successfully treat
sarcopenia or cachexia. Hence combination therapies have been pro-
posed, including eicosapentaenoic acid and training exercise [90,91],
as well as anabolic steroids and exercise or more complex combina-
tions like megestrol acetate plus L-carnitine, celecoxib, and possibly
also antioxidants [92,93]. A corner-stone of therapeutic research in
cachexia and sarcopenia has been nutritional studies. Rozentryt and
colleagues performed a clinical trial of nutritional intervention in car-
diac cachexia [94]. A diet containing 600 kcal per day for 6 weeks
(with relatively high fat content to reduce volume) increased weight
during the treatment and the subsequent 12-week follow-up period
(70% fat tissue, 30% muscle tissue) and had anti-inflammatory effects
(reduction of TNF levels). This was accompanied by increases in cho-
lesterol levels. The quality of life of patients improved for the 6 weeks
of the period of the nutritional intervention, but decreased somewhat
in the additional follow-up period.
Starting in 2008 [95] and with much more intensity in 2010 to
2012, a number of consensus-building activities to define cachexia
and sarcopenia have been undertaken [96–99]. Also a more specific
consensus document on the definition and stages of cancer cachexia
has been published [100]. The reason for these activities is that it
has been argued that treatments for cachexia (or sarcopenia) can
only be developed when one can define it [101]. As much as this
may be true, defining cachexia is not a simple task [102], and one
can also postulate that inclusion and exclusion criteria of trials per
se are at least as much important as consensus definitions may in
the long-term be. If they lead to regulatory treatment approval, then
they will build the fundamental for approved educational initiatives
that may likely develop more disease defining power than the con-
sensus definitions ever could.
This may be similar to the situation regarding the definition of di-
astolic heart failure or HF with preserved ejection fraction [103,104].
Guidelines and consensus papers will not be as powerful as the first
successful therapies and the inclusion and exclusion criteria they
used.
3. Journal and conference activities
Finally, the field of cachexia, sarcopenia and muscle wasting re-
search is characterised by the development of several new scientific
journals. In 2010, we founded the Journal of Cachexia, Sarcopenia
and Muscle (JCSM). In 2011, the journal Skeletal Muscle, and in 2012
The Journal of Frailty & Aging (JFA) were founded. All these journals
are free access or open access. Since 2000, six international cachexia
conferences have taken place and reported extensively. Since 2000,
the number of attendees has steadily increased from 150 to more
than 400 in 2009 [105]. The next conference will take place on 8–11
December, 2013. Of even greater interest may be to those involved
in the treatment development for cachexia and muscle wasting in
HF is the 2013 Annual Congress of the Heart Failure Association of
the European Society of Cardiology (Lisbon, 25–28 May, 2013),
where on 28/29 May a trialist workshop on treatment development
for cachexia and muscle wasting in heart failure and chronic obstruc-
tive pulmonary disease will be held.
Acknowledgment
SvH is a consultant and has received honoraria for speaking from
Professional Dietetics, Vifor, and Pfizer. SDA is a consultant, has re-
ceived honoraria for speaking and/or has attended advisory boards
 M.S. Anker et al. / International Journal of Cardiology 162 (2013) 73–76
for Amgen Inc., Professional Dietetics, Psioxus Therapeutics, GTx,
Helsinn, GSK, Sanofi, Regeneron, Novartis, Takeda, Servier, Chugai
and Vifor. All other authors report no conflict of interest. The authors
of this manuscript have certified that they comply with the Principles
of Ethical Publishing in the International Journal of Cardiology.
This paper is also published in parallel in Archives of Medical
Science
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